Nitrone, Nitroso, and Nitroxide Spintraps and Spin Labels and Their Hydroxylamines

ABSTRACT

Nitrone, nitroso, and nitroxide spintraps and spin labels and their reduction products are claimed for the prevention and treatment of fibrocystic disease of breast, premenstrual dysphoric syndrome and associated symptomology, prevention and treatment of migraine headache, cyclic vomiting syndrome, rectal hemorrhoids, trigeminal neuralgia, peripheral vascular disease, influenza, peridontitis and gingivitis, herpes zoster, herpes simplex, and post-herpetic neuralgia.

CITATIONS

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PARENT CASE TEXT Related Applications

The present application claims priority to U.S. Provisional ApplicationNo. 6,125,913, filed Nov. 7, 2009.

FIELD OF THE INVENTION

The present invention is directed to methods that treat, prevent,inhibit, or slow the development of fibrocystic disease of breast,rectal hemorrhoids, gingivitis and peridontitis, migraine headache,perimenstrual dysphoric disorder, cyclic vomiting syndrome, herpeszoster, and post-herpetic neuralgia and trigeminal neuralgia, and thesymptoms of influenza in humans The inventive methods comprise theadministration of pharmaceutical preparations comprising nitorne,nitroxide and nitroso compounds and their corresponding reductionproducts orally, intraorally, systemically by injection, and by localrectal administration.

BACKGROUND OF THE INVENTION

Various publications, including patents, published applications, andscholarly or technical articles are cited above and throughout thespecification. Each of the cited publications is incorporated byreference herein, in its entirety.

DESCRIPTION

Fibrocystic disease of the breast in women is a chronicpotentially-debilitating disease associated with significant morbidity,especially pain and discomfort. Generally considered a benign condition,the existence of breast cysts can interfere with the diagnosis of breastcancer. To date, other than simple palliation, the only treatment per sefor fibrocystic disease of breast has been surgical excision of thecysts. In some cases, this can include complete mastectomy. Similarly,trigeminal neuralgia and postherpetic neuralgia are significant causesof pain and disability. Peridontitis and gingivitis are significantcauses of tooth loss, pain and discomfort. The efficacy of variousnitrone, nitroso, and nitroxide spin traps and spin labels and theirequivalent reduction products in some model diseases in experimentalanimals has long been recognized. However, studies with such antioxidantdrugs have not well translated to humans. E.g., with respect toneuroprotection, in general and nitrone and nitroxide drugs inparticular: “There are hundreds, perhaps thousands of neuroprotectivedrugs that have been used in animal models. So, if you were a mouse or arat, and experienced a stroke or cardiac arrest, we would know just whatto do for you. But, essentially none of these pharmacological agentshave demonstrated usefulness in humans even though they have been shownto be successful in preclinical animal trials” (Traystman R J.Neuroprotection: introduction. Stroke. 2010 October; 41(10 Suppl):S63.).In particular, one such neuroprotective agent effective in animalmodels, but not in humans, is the phenybutylnitrone derivative NXY-059.

Moreover, in animals treatment effects are reported at systemic humanequivalent doses orders of magnitude higher than we found efficacy in(e.g.) fibrocystic disease in humans. If the in vivo active form is(say) the reduced derivative, this may be an unexpected consequence ofthe presence in humans and higher primates of singularly high levels ofthe powerful reducing substance uric acid. Paradoxically, since itcompetes with them for action, the singularly-high level of urate inhumans may also may explain the perpetual failure of antioxidant drugssuch as NXY-059 in human clinical trials, even at several grams per daydoses (Proctor P H. Uric acid and neuroprotection. Stroke. 2008 August;39(8):e126.). That is, any systemic efficacy of such nitrone, nitroso,and nitroxide drugs in humans, much less efficacy at very low doses, isunexpected.

Similarly, we recognized the potential benefit of administering suchcompounds topically in their reduced forms (U.S. Pat. Nos. 5,714,482,5,714,510, 5,716,947, 5,723,502, 5,728,714), e.g., in presence of astrong reducing compound such as ascorbic acid. For one thing,coadministration in the reduced form or in the presence of a reducingsubstances may prevent depletion of endogenous reducing equivalents bythe parent drugs. These patents are here-by incorporated by reference.However, the efficacy, much less the benefits, of the using such reducedforms is disputed. E.g., Hsia et al (U.S. Pat. No. 7,314,633) note that“If a nitroxide is reduced to a hydroxylamine it loses its ability tomodulate reactions. By positioning the nitroxide between two carboxylicacid groups a “gating” effect is obtained, i.e. the nitroxide isprotected and its ability to modulate reactions is maintained over alonger period of time in a greater range of in vivo environments ascompared to a molecule lacking the carboxylic acid groups.”

Moreover, because there is no good animal model for fibrocystic diseaseof breast, such agents have never been considered for the treatment ofthis condition. Similarly, for lack of animal models, recognition of theefficacy of such compounds in post-herpetic neuralgia, rectalhemorrhoids, and peridontitis/gingiyitis had to await the use of suchcompounds in persons with the actual human disease. The same is true forthe diseases claimed in this patent, including fibrocystic disease ofbreast, perimenstrual dysphoric syndrome, prevention and treatment ofmigraine headache, peripheral artery disease, post-herpetic andtrigeminal neuralgia, cyclic vomiting syndrome, and influenza. In fact,previously, the only human use of (e.g.) TEMPOL was experimental topicaltreatment to ameliorate radiation injury (Wilcox, 2010).

However, in the course of extemporaneous treatment with an oralformulation of the reduced form of TEMPOL (TEMPOL-H), we unexpectedlyobserved and documented almost complete regression of long-standing andintractable fibrocystic disease in a 48-year-old female patient.

Unexpectedly, we also found treatment with the same formulation (orTEMPOL itself) to ameliorate influenza, peridontitis and gingivitis,rectal hemorrhoids, trigeminal neuralgia, premenstrual dysphoricsyndrome and its associated comorbid symptoms, to both to prevent andtreat migraine headache, and to prevent and treat herpes zoster lesionsand post-herpetic neuralgia in humans.

Definitions:

The term “nitroxide”, “nitron”, and “nitroso” are used herein todescribe molecules comprising an oxygen and a nitrogen atom directlybound to each other. These compounds may be a electron donors oracceptors. Depending on their oxidation state, these compounds maycomprise stable nitroxyl free radicals, including precursors (such asthe N—H form), and derivatives thereof including their correspondinghydroxylamine derivative (N—OH), where the oxygen atoms are replacedwith a hydroxyl group and/or exist in a hydrogen halide form.

Nitroxides and nitrones of the invention may be administered to asystem, such as a human, and act to modulate oxidation and reductionreactions by donating or accepting an electron. Other mechanisms mayinclude formation of charge-transfer complexes as well as by “redoxsignaling” or modulation of redox-signaling-mediated processes.Stability of unpaired electrons on such compounds is typically-providedat the nitrogen nucleus by two adjacent carbon atoms that may besubstituted with strong electron donor groups. With the partial negativecharge on the oxygen of the N—O bond, the two adjacent carbon atomstogether localize the unpaired electron on the nitrogen nucleus.Nitroxides and nitrones generally may have either a heterocyclic or alinear structure. In an vivo environment a nitroxide may react with afirst superoxide to form oxoammonium (as an electron donor) and thenreact with a second superoxide to re-form the nitroxide (as an electronacceptor). (Review: Wilcox C S. Effects of tempol and redox-cyclingnitroxides in models of oxidative stress. Pharmacol Ther. 2010 May;126(2):119-45.)

The terms “treat,” “treatment” and the like are used herein to generallymean obtaining a desired pharmacological and/or physiological effect inhumans or other animals. A treatment is an approach for obtainingbeneficial or desired clinical results. While the claims are notdependent on any specific mechanism, in the present case, these clinicalresults include but are not limited to decreasing undesirable effects ofreactive oxygen species (ROS) and oxidative stress in general, as wellas modulating more specific messenger processes such as “redoxsignaling”. The effect may be prophylactic in terms of completely orpartially preventing a disease and/or symptom thereof and/or may betherapeutic in terms of a partial or complete cure of the disease and/oradverse effect attributed to the disease. In general, methods of theinvention may be applied to a variety of different areas including theskin, mucus membranes including those in the GI tract, nose, throat,mouth, vaginal cavity, ocular surfaces, as well as the surfaces of thelungs and the surfaces of the vascular system as well as systemically bymeans of intravenous, intraocular, intramuscular, transdermal,sublingual, and/or intraoral administration. “Treatment” as used hereincovers any treatment of such a symptom or disease in a mammal,particularly a human, and includes:

(a) preventing or diagnosing the disease and/or symptoms in the subjectwhich may be predisposed to the disease and/or symptom but has not yetbeen diagnosed as having it;

(b) inhibiting the disease, i.e. arresting it's development; and/or

(c) relieving the disease and/or it's symptom, i.e. causing regressionof the disease and/or the symptoms caused by the disease.

Exemplar Nitrone and nitroxide spin traps and spin labels include, butare not limited to, DEPMPO (5-(Diethoxyphosphoryl)-5-methyl-1-pyrrolineN-oxide), TEMPO (2,2,6,6-tetramethyl-1-piperidinyl-1-oxyl),4-Amino-TEMPO, 4-hydroxy-TEMPO (TEMPOL), DMPO(5,5-dimethylpyrroline-N-oxide), EMPO(2-Ethoxycarbonyl-2-methyl-3,4-dihydro-2H-pyrrole-1-oxide), POBN(alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone), TEMPONE(4-Oxo-2,2,6,6-tetramethylpiperidine-1-oxyl 4-Oxo-TEMPO), TMIO,3,3,5,5tetramethyl-1-pyrolline-N-oxide (TMPO), M3PO(2,5,5-trimethyl-1-pyrroline-N-oxide), M4PO(3,3,5,5-tetramethyl-1-pyrroline-N-oxide), TMPO (3,3,5,5tetramethyl-1-pyrolline-N-oxide), PBN (1-alpha-phenyl-tert-butylnitrone), and MNP (2-methyl-2-nitrosopropane), as well as theircorresponding hydroxylamine derivatives. The various sulfone (e.g.,NXY-059, disulfonyl PBN), hydroxyl, and other derivatives such asesters, peptides, hydroxyl, hydroxylamines, nitrones, carboxyls, and soforth are also claimed.

Preferred examples of the type of hydroxylamine compounds suitable foruse in the present invention are TEMPOL-H ((the hydroxylamine reducedform of the nitroxide 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-yloxy),TEMPO-H (the hydroxylamine reduced form of the nitroxide2,2,6,6-tetramethylpiperidin-1-yloxy) and OXANO-H(2-ethyl-2,4,4-trimethyloxazolidine, which is the reduced form of oxano,2-ethyl-2,4,4-trimethyloxazolidin-3-yloxy). Other hydroxylaminecompounds suitable for use in the present invention include, but are notlimited to, those disclosed by Hahn et al. (1998, supra; 2000, supra),Samuni et al. (2001, supra); and in U.S. Pat. No. 5,981,548 to Paolini,et al. (disclosing certain N-hydroxylpiperidine esters and their use asantioxidants in a number of contexts); U.S. Pat. No. 4,404,302 to Guptaet al. (disclosing the use of certain N-hydroxylamines as lightstabilizers in plastics formulations); U.S. Pat. No. 5,462,946 toMitchell et al. (disclosing certain nitroxides deriving from substitutedoxazolidines for protection of organisms from oxidative stress); U.S.Pat. No. 3,936,456 to Ramey et al. (disclosing substituted piperazinedione oxyls and hydroxides for the stabilization of polymers); U.S. Pat.No. 4,691,015, to Behrens et al. (describing hydroxylamines derived fromhindered amines and the use of certain of them for the stabilization ofpolyolefins); and the hydroxylamine compounds disclosed, in the severalaforementioned U.S. patents to Hsia et al. Most of the above-referencedcompounds have not been known heretofore for administration to humans.Certainly, none of them has been known for use in the treatment offibrocystic disease of the breast, rectal hemorrhoids, menstrualdysphoric syndrome, migraine, the symptoms of influenza, herpes zosterand post herpetic neuralgia, or trigeminal neuralgia. Suitable reducingagents include, but are not limited to: ascorbic acid, lipoic acid,cystine, purines and derivatives such as acetylcysteine, uric acid andother oxyxanthines, methionine, homocysteine, NADPH, NADH, and so forth.

Examples Preparation of a Therapeutic Solution of Reduced TEMPOL

The reduced form of TEMPOL (TEMPOL-H) or equivalentpharmacologically-active spin label/spintrap is prepared by mixingtogether 2 grams of TEMPOL or a pharmacologically effective amount ofanother spin-label or spin trap such as methynitrosopropane, 20 grams ofascorbic acid or other reducing compound in 100 ml of distilled water.The formulation is used as is. The solution is slightly-bitter. Theformulation can be administered diluted in a suitable liquid such asjuice, tea, or coffee. An equivalent dry form as 10 mg of tempol mixedwith 100 mg of acsorbic acid or equivalent reducing substance can beeasily prepared in capsule or tablet form.

Treatment of Fibrocystic Disease or Breast

One-half ml of the above solution, comprising 10 mg TEMPOL plus 100 mgascorbic acid, was administered orally once a day to a 50 kg woman witha long history for fibrocystic disease of breast so severe that surgeonshad recommended mastectomy. The same person had also beenpreviously-diagnoses with severe trigeminal neuralgia.

First results appeared after 1-2 weeks of treatment and involveshrinkage of the breast cysts, as verified by before and aftermammographic imaging, and digital palpation. Long-term relief can beachieved, but the symptoms eventually reappear on cessation of treatmentfor a few weeks. Upon resumption of treatment, symptoms the breast cystsagain drastically shrink. The patient had also suffered fromlong-standing trigeminal neuralgia which was also alleviated andprevented.

Alternate forms of oral administration such as tablets, pills orcapsules are also effective. Parental modes of administration such asintravenous, intramuscular, subcutaneous, intraperitoneal, transrectaland so forth are also possible, as are topical modes of administrationsuch as in lotions, creams, gels, and topically-compatible suspensionsand solutions. Tempol itself is effective at the same doses, but mayhave increased side-effects at higher doses, e.g., due to oxidation ofreducing agents or production of hydrogen peroxide.

Treatment of Premenstrual Dysphoric Disorder

In this patient, the above treatment also alleviates and prevents thesymptoms of premenstrual dysphoric disorder including comorbidity suchas unipolar depression and anxiety, mood swings, difficultyconcentrating and fatigue, as well as physical symptoms such asbloating, breast tenderness, headaches, and joint or muscle pain.Efficacy was observed in ameliorating symptoms of anxiety/depression andmood swings outside the premenstrual time period.

Treatment of Migraine Headache

The above treatment both prevents migraine headache and ameliorates thesymptoms of migraine headache.

Treatment of Cyclic Vomiting Syndrome

The above treatment both prevents, controls, and ameliorates cyclicvomiting syndrome.

Treatment of Peripheral Vascular Disease

The above treatment controls, and ameliorates peripheral vasculardisease/

Treatment of Post-Herpetic Neuropathy

One-half ml of the above solution was orally-administered daily to amiddle-aged male with chronic post-herpetic neuropathy of the feet,peridontitis, and gingivitis. Symptomatic relief of all of these wasexperienced within one week of starting treatment. Topical applicationof the above formulation once a day to the affected area is alsoeffective in post-herpetic neuralgia, as well as in the treatment ofherpes zoster lesions. Topical application was also effective in thetreatment of gingivitis and peridontitis.

Amelioration of Influenza Symptomology

One-half ml of the above formulation of TEMPOL-H administered orallyonce or twice daily also significantly-ameliorates the symptoms ofinfluenza. 0.1 ml applied locally to the nasal cavity amelioratesrhinositis.

Treatment of Rectal Hemorrhoids

Prepare:

5 grams methyl Cellulose

100 ml water

Boil until methycellulose dissolves (5-10 minutes)

Alternative is I million-dalton MW 1% propylcellulose, which dissolvesovernight without boiling.

Add 5 grams TEMPOL with stirring

Allow to gel.

0.2 ml of this 5% solution of TEMPOL or the appropriate reduced formadministered transrecally for one to three days ameliorates the symptomsof rectal hemorrhoids, especially pain, swelling, and bleeding.

Intraoral Treatment of Gingivitis and Peridontitis

The above anti-hemorrhoidal formulations are also helpful in the localtreatment of gingivitis and peridontitis, specifically reducingtenderness and bleeding Treatment is 0.5 ml of the 5% TEMPOL liquid orgel applied to the affected gums for one to three days.

The proper dosage, optimal number of times to administer the compound(daily, weekly, etc.), and length time in which the parent compoundsand/or their hydroxylamines must be administered to the subject as partof a follow-up regimen will be empirically determined by methods thatare routine in the art, and may vary with the needs of individualsubjects.

The present invention is not limited to the embodiments described andexemplified above, but is capable of variation and modification withinthe scope of the appended claims. Also, the claims are not bound by anysuggested possible mechanism of action and are independent thereof.

Those skilled in the art will appreciate that numerous changes andmodifications can be made to the preferred embodiments of the inventionand that such changes and modifications can be made without departingfrom the spirit of the invention. It is, therefore, intended that theappended claims cover all such equivalent variations as fall within thetrue spirit and scope of the invention. Likewise, each claim andindication stands independent of the patentability or patent status ofany other claim and indication.

1. Treatment of fibrocystic disease of breast with a nitrone, nitroso,or nitroxide spin trap or spin label or their reduced forms at apharmacologically-effective dose.
 2. Prevention and treatment ofperimenstral dysphoric syndrome with a nitrone, nitroso, or nitroxidespin trap or spin label or their reduced forms at apharmacologically-effective dose.
 3. Treatment of rectal hemorrhoidswith a nitrone, nitroso, or nitroxide spin trap or spin label and/ortheir reduced forms at a pharmacologically effective dose administeredtopically and/or systemically.
 4. Treatment of herpes zoster and/orpost-herpetic neuralgia or related conditions with a nitrone, nitroso,or nitroxide spin-trap or a spin label and/or the reduced form of suchat a pharmacologically effective dose, administered topically and/orsystemically.
 5. Treatment of peridontitis and/or gingivitis with anitrone or nitroso spin trap or nitroxide spin label or its reduced format a pharmacologically-effective dose administered topically and/orsystemically.
 6. Treatment of the symptoms of influenza with a nitronespin trap or nitroxide spin label or their reduced forms at apharmacologically-effective dose administered topically and/orsystemically.
 7. Prevention and treatment of migraine headache with anitrone, nitroso, or nitroxide spin trap or spin label or their reducedforms at a pharmacologically-effective dose.
 8. Prevention and treatmentof cyclic vomiting syndrome with a nitrone or nitroso spin trap ornitroxide spin label or its reduced form at apharmacologically-effective dose administered topically and/orsystemically.
 9. Treatment of the above where the nitroxide is TEMPO(2,2,6,6-tetramethyl-1-piperidinyl-1-oxyl) or a derivative. Thisincludes 4-hydroxy-TEMPO (TEMPOL), 4 amino-TEMPO and/or their reducedderivatives such as TEMPO-H or TEMPOL-H.
 10. Treatment of the abovewhere the nitroxide, nitrone, or nitroso compound is 2-methyl,2-nitrosopropane, its derivatives, or their reduced forms.
 11. Treatmentof the above where the pharmacologically-active dose is 0.01-1000 mg perday of a pharmacologically-active nitroxide, nitrone, or nitrosospin-trap, spin label or their equivalent hydroxylamine and otherreduced derivatives administered by suitable means such as orally,sublingually, transrectally, intramuscularly, intravenously, orsubcutaneously.
 12. Treatment of the above conditions where thenitroxide, nitrone, or nitroso spin trap or spin label is administeredalong with a reducing agent.
 13. Treatment of the above conditions wherethe pharmacologically-effective dose is 0.01 to 1 mg/kg
 14. Treatment ofthe above conditions where the pharmacologically-effective dose is 1 to10 mg/kg
 15. Treatment of the above conditions where thepharmacologically-effective dose is 10 mg/kg to 100 mg/kg.
 16. Treatmentof the above conditions where the pharmacologically-effective dose is100 to 1000 mg/kg.
 17. Treatment of the above where the reducingsubstance is ascorbic acid, uric acid, cysteine, acetylcysteine, lipoicacid, vitamin-E, carnitine, acetylcarnitine, NADH, or NADPH, or theirderivatives, present at amounts from 0.01 to 1000 mg/kg.
 18. Treatmentof the above where the reducing substance is anyphysiologically-compatible substance capable of reducing the nitroxide,nitroso, or nitrone compound to a hydroxylamine derivative or ofrereducing a physiological reducing agent that reduces the nitroxide,nitroso, or nitrone, present at amounts from 0.01 to 1000 mg/kg.